The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. � 2016 American Association for Cancer Research

Cellular immune responses against the tumour associated polymorphic epithelial mucin MUC1

Available from British Library Document Supply Centre-DSC:DXN053092 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Deep ion sequencing of amplicon adapter ligated libraries: a novel tool in molecular diagnostics of formalin fixed and paraffin embedded tissues

Due to the advanced progress in personalised therapy concepts for non-small cell lung cancer (NSCLC), we applied the ion semiconductor sequencing (ISS) approach to molecular diagnosis of NSCLC, analysing a set of therapy relevant gene loci. DNA from macrodissected tumour samples of formalin fixed biopsies was used for PCR amplification of EGFR exons 18, 19, 21 and KRAS exon 1. A total of 128 PCR products were analysed by conventional termination sequencing as well as by ISS. Sensitivity of ISS was additionally determined using 100–10 000 copies of reference mutants. All somatic mutations detected by direct Sanger sequencing were also identified by ISS. No additional mutants were detected. Running samples with limited copies of mutated alleles revealed high sensitivity, detecting less than 10% (2500 copies) mutants in a human wild type background. In conclusion, multiplexed mutation analyses by ISS is an efficient technology that can easily be linked to existing PCR approaches in molecular pathology

Supplementary Material for: Alterations of Global Histone H3K9 and H3K27 Methylation Levels in Bladder Cancer

<b><i>Background:</i></b> Epigenetic alterations, including histone modifications, play an important role during carcinogenesis. This study was designed to systematically investigate histone H3K9 and H3K27 methylation levels in bladder cancer (BCa) tissue. <b><i>Methods:</i></b> A tissue microarray with urothelial BCa (150 non-muscle-invasive BCa, NMIBC; 121 muscle-invasive BCa, MIBC; 31 metastatic BCa, MET) and normal urothelium (29, CTRL) specimen was used to determine the global levels of H3K9 and H3K27 mono-, di- and tri-methylation. <b><i>Results:</i></b> Global levels of H3K9 and H3K27 methylation were significantly higher in CTRL than in BCa, and levels in NMIBC were higher compared to MIBC. Histone methylation levels of MET resembled MIBC. We observed furthermore a correlation of histone methylation levels with pT stage (H3K9me1, H3K9me2, H3K9me3, H3K27me1, H3K27me3) and grade (H3K9me2, H3K9me3, H3K27me1) in NMIBC. H3K9me1, H3K9me3, H3K27me1 and H3K27me3 levels were also correlated with pT stage in MIBC. Histone modifications were not associated with recurrence-free or cancer-specific survival. <b><i>Conclusions:</i></b> Global histone H3K9 and H3K27 methylation levels are altered in BCa

Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors

PURPOSE: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). EXPERIMENTAL DESIGN: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models. RESULTS: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRAS(G12S) mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS CONCLUSIONS: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies

MUC1 Story: Great Expectations, Disappointments and the Renaissance

International audienc